Mathematical models on the impact of noise and dyadic molecular structures on the properties of a cardiac myocyte

In cardiac myocytes (heart muscle cells), coupling of electric signal known as the action potential to contraction of the heart depends crucially on calcium-induced calcium release (CICR) in a microdomain known as the dyad. During CICR, the peak number of free calcium ions (Ca) present in the dyad is small, typically estimated to be within range 1-100. Since the free Ca ions mediate CICR, noise in Ca signaling due to the small number of free calcium ions influences Excitation-Contraction (EC) coupling gain. Noise in Ca signaling is only one noise type influencing cardiac myocytes, e.g., ion channels playing a central role in action potential propagation are stochastic machines, each of which gates more or less randomly, which produces gating noise present in membrane currents. How various noise sources influence macroscopic properties of a myocyte, how noise is attenuated and taken advantage of are largely open questions. In this thesis, the impact of noise on CICR, EC coupling and, more generally, macroscopic properties of a cardiac myocyte is investigated at multiple levels of detail using mathematical models. Complementarily to the investigation of the impact of noise on CICR, computationally-efficient yet spatially-detailed models of CICR are developed. The results of this thesis show that (1) gating noise due to the high-activity mode of L-type calcium channels playing a major role in CICR may induce early after-depolarizations associated with polymorphic tachycardia, which is a frequent precursor to sudden cardiac death in heart failure patients; (2) an increased level of voltage noise typically increases action potential duration and it skews distribution of action potential durations toward long durations in cardiac myocytes; and that (3) while a small number of Ca ions mediate CICR, Excitation-Contraction coupling is robust against this noise source, partly due to the shape of ryanodine receptor protein structures present in the cardiac dyad.

Bayesian statistical analysis of bacterial diversity

Bacteria play an important role in many ecological systems. The molecular characterization of bacteria using either cultivation-dependent or cultivation-independent methods reveals the large scale of bacterial diversity in natural communities, and the vastness of subpopulations within a species or genus. Understanding how bacterial diversity varies across different environments and also within populations should provide insights into many important questions of bacterial evolution and population dynamics. This thesis presents novel statistical methods for analyzing bacterial diversity using widely employed molecular fingerprinting techniques. The first objective of this thesis was to develop Bayesian clustering models to identify bacterial population structures. Bacterial isolates were identified using multilous sequence typing (MLST), and Bayesian clustering models were used to explore the evolutionary relationships among isolates. Our method involves the inference of genetic population structures via an unsupervised clustering framework where the dependence between loci is represented using graphical models. The population dynamics that generate such a population stratification were investigated using a stochastic model, in which homologous recombination between subpopulations can be quantified within a gene flow network. The second part of the thesis focuses on cluster analysis of community compositional data produced by two different cultivation-independent analyses: terminal restriction fragment length polymorphism (T-RFLP) analysis, and fatty acid methyl ester (FAME) analysis. The cluster analysis aims to group bacterial communities that are similar in composition, which is an important step for understanding the overall influences of environmental and ecological perturbations on bacterial diversity. A common feature of T-RFLP and FAME data is zero-inflation, which indicates that the observation of a zero value is much more frequent than would be expected, for example, from a Poisson distribution in the discrete case, or a Gaussian distribution in the continuous case. We provided two strategies for modeling zero-inflation in the clustering framework, which were validated by both synthetic and empirical complex data sets. We show in the thesis that our model that takes into account dependencies between loci in MLST data can produce better clustering results than those methods which assume independent loci. Furthermore, computer algorithms that are efficient in analyzing large scale data were adopted for meeting the increasing computational need. Our method that detects homologous recombination in subpopulations may provide a theoretical criterion for defining bacterial species. The clustering of bacterial community data include T-RFLP and FAME provides an initial effort for discovering the evolutionary dynamics that structure and maintain bacterial diversity in the natural environment.

Data mining for telecommunications network log analysis

Telecommunications network management is based on huge amounts of data that are continuously collected from elements and devices from all around the network. The data is monitored and analysed to provide information for decision making in all operation functions. Knowledge discovery and data mining methods can support fast-pace decision making in network operations. In this thesis, I analyse decision making on different levels of network operations. I identify the requirements decision-making sets for knowledge discovery and data mining tools and methods, and I study resources that are available to them. I then propose two methods for augmenting and applying frequent sets to support everyday decision making. The proposed methods are Comprehensive Log Compression for log data summarisation and Queryable Log Compression for semantic compression of log data. Finally I suggest a model for a continuous knowledge discovery process and outline how it can be implemented and integrated to the existing network operations infrastructure.

Viivesietoisten verkkojen nykytila ja tulevaisuuden haasteet

Delay and disruption tolerant networks (DTNs) are computer networks where round trip delays and error rates are high and disconnections frequent. Examples of these extreme networks are space communications, sensor networks, connecting rural villages to the Internet and even interconnecting commodity portable wireless devices and mobile phones. Basic elements of delay tolerant networks are a store-and-forward message transfer resembling traditional mail delivery, an opportunistic and intermittent routing, and an extensible cross-region resource naming service. Individual nodes of the network take an active part in routing the traffic and provide in-network data storage for application data that flows through the network. Application architecture for delay tolerant networks differs also from those used in traditional networks. It has become feasible to design applications that are network-aware and opportunistic, taking an advantage of different network connection speeds and capabilities. This might change some of the basic paradigms of network application design. DTN protocols will also support in designing applications which depend on processes to be persistent over reboots and power failures. DTN protocols could also be applicable to traditional networks in cases where high tolerance to delays or errors would be desired. It is apparent that challenged networks also challenge the traditional strictly layered model of network application design. This thesis provides an extensive introduction to delay tolerant networking concepts and applications. Most attention is given to challenging problems of routing and application architecture. Finally, future prospects of DTN applications and implementations are envisioned through recent research results and an interview with an active researcher of DTN networks.

Sankarihautaus vapaussodassa : valkoisten kaatuneiden hautaaminen Suomessa vuonna 1918

Civil War Hero Burials the funerals of the fallen White in Finland in 1918 This study focuses on the burial with honours of fallen White combatants during the Finnish Civil War of 1918, as well as on the reasons underpinning the practice. The main sources of the study included the archives of the White army, the Civil Guard organisation and the Church, as well as the newspapers. The genetic method of history research was used. Both the existing tradition of military burials and the ecclesiastical burial culture influenced the burials of those who fell during the Civil War. The first war hero funerals took place as early as the beginning of February 1918, and the first larger-scale collective funerals were organised in Laihia and Vaasa in the Ostrobothnia province, with the latter attended by the supreme civil and military leaders of White Finland. From early on, these funerals assumed their characteristic features, such as the lion flag a design for the Finnish national flag proposed immediately upon the declaration of the country s independence military parades, lines of honour guards, eulogies, salutes and common war hero graves. As a result of the general offensive begun in mid-March 1918, the numbers of the fallen multiplied, so special organisations were established to handle the burials of the fallen. At the same time, the war hero funerals became more frequent and diffused, and the numbers of the buried grew throughout the country. In early March, the advocates of the republican system of government published their appeal in the newspapers, requesting that collective graves for those who fell in the war prepared in every locality. They motivated their request by stating that it was the funerals in particular that had inspired many men to join the ranks voluntarily in the first place, and that the large collective soldiers graves increased the numbers of those who answered the call and left for the front. The Civil Guard organisation arranged the burials of war heroes. The clergy contributed by officiating the religious service and by clearly aligning themselves with the Whites in their eulogies. The teachings of the Lutheran Church suggest that they found the Whites to be the temporal authority instituted by God, and therefore authorised raising the sword against the Reds. Speaking at the funerals with great pomp and sentimental power, the leaders of the Civil Guard and the exponents of the learned classes instigated their audiences against the Reds. The funeral speeches idealised the war hero s death by recalling military history since the times of ancient Greece. Being of the emblematic colour of the Whites, the white coffin assumed a particular importance connected to ideas of biblical purity and innocence. By the end of May 1918, almost 3,300 Whites were buried in the soldiers graves prepared by the burial organisation in some 400 localities. Only about 200 men remained missing in action or unidentified. The largest common graves accommodated over 60 fallen combatants. Thus, the traditions of the 1918 Civil War directly influenced war hero burial practices, which continued into the Finnish Winter War of 1939.

Essays on corporate governance, stakeholders, and restructuring

This dissertation consists of an introductory section and three theoretical essays analyzing the interaction of corporate governance and restructuring. The essays adopt an incomplete contracts approach and analyze the role of different institutional designs to facilitate the alignment of the objectives of shareholders and management (or employees) over the magnitude of corporate restructuring. The first essay analyzes how a firm's choice of production technology affects the employees' human capital investment. In the essay, the owners of the firm can choose between a specific and a general technology that both require a costly human capital investment by the employees. The specific technology is initially superior in using the human capital of employees but, in contrast to the general technology, it is not compatible with future innovations. As a result, anticipated changes in the specific technology diminish the ex ante incentives of the employees to invest in human capital unless the shareholders grant the employees specific governance mechanisms (a right of veto, severance pay) so as to protect their investments. The results of the first essay indicate that the level of protection that the shareholders are willing to offer falls short of the socially desirable one. Furthermore, when restructuring opportunities become more abundant, it becomes more attractive both socially and from the viewpoint of the shareholders to initially adopt the general technology. The second essay analyzes how the allocation of authority within the firm interacts with the owners' choice of business strategy when the ability of the owners to monitor the project proposals of the management is biased in favor of the status quo strategy. The essay shows that a bias in the monitoring ability will affect not only the allocation of authority within the firm but also the choice of business strategy. Especially, when delegation has positive managerial incentive effects, delegation turns out to be more attractive under the new business strategy because the improved managerial incentives are a way for the owners to compensate their own reduced information gathering ability. This effect, however, simultaneously makes the owners hesitant to switch the strategy since it would involve a more frequent loss of control over the project choice. Consequently, the owners' lack of knowledge of the new business strategy may lead to a suboptimal choice of strategy. The third essay analyzes the implications of CEO succession process for the ideal board structure. In this essay, the presence of the departing CEO on the board facilitates the ability of the board to find a matching successor and to counsel him. However, the ex-CEO's presence may simultaneously also weaken the ability of the board to restructure since the predecessor may use the opportunity to distort the successor's project choice. The results of the essay suggest that the extent of restructuring gains, the firm's ability to hire good outside directors and the importance of board's advisory role affect at which point and for how long the shareholders may want to nominate the predecessor to the board.

Effects of environmental variation on ecological and evolutionary dynamics

Environmental variation is a fact of life for all the species on earth: for any population of any particular species, the local environmental conditions are liable to vary in both time and space. In today's world, anthropogenic activity is causing habitat loss and fragmentation for many species, which may profoundly alter the characteristics of environmental variation in remaining habitat. Previous research indicates that, as habitat is lost, the spatial configuration of remaining habitat will increasingly affect the dynamics by which populations are governed. Through the use of mathematical models, this thesis asks how environmental variation interacts with species properties to influence population dynamics, local adaptation, and dispersal evolution. More specifically, we couple continuous-time continuous-space stochastic population dynamic models to landscape models. We manipulate environmental variation via parameters such as mean patch size, patch density, and patch longevity. Among other findings, we show that a mixture of high and low quality habitat is commonly better for a population than uniformly mediocre habitat. This conclusion is justified by purely ecological arguments, yet the positive effects of landscape heterogeneity may be enhanced further by local adaptation, and by the evolution of short-ranged dispersal. The predicted evolutionary responses to environmental variation are complex, however, since they involve numerous conflicting factors. We discuss why the species that have high levels of local adaptation within their ranges may not be the same species that benefit from local adaptation during range expansion. We show how habitat loss can lead to either increased or decreased selection for dispersal depending on the type of habitat and the manner in which it is lost. To study the models, we develop a recent analytical method, Perturbation expansion, to enable the incorporation of environmental variation. Within this context, we use two methods to address evolutionary dynamics: Adaptive dynamics, which assumes mutations occur infrequently so that the ecological and evolutionary timescales can be separated, and via Genotype distributions, which assume mutations are more frequent. The two approaches generally lead to similar predictions yet, exceptionally, we show how the evolutionary response of dispersal behaviour to habitat turnover may qualitatively depend on the mutation rate.

Spatial and temporal determinants of Finnish farmland bird populations

During the past decades agricultural intensification has caused dramatic population declines in a wide range of taxa related to farmland habitats, including farmland birds. In this thesis, I studied how boreal farmland landscape characteristics and agricultural land use affect the abundance and diversity of farmland birds using extensive field data collected by territory mapping of breeding farmland birds in various parts of Finland. My results show that the area and openness of agricultural areas are key determinants of farmland bird abundance and distribution. A landscape composition with enough open farmland combined with key habitats such as farmyards and wetland is likely to provide essential prerequisites for the occurrence of a rich farmland avifauna. In Finland, the majority of large areas suitable for open habitat specialists are located in southern and western parts of the country. However, the diversity of the species with an unfavourable conservation status in Europe (SPECs) had notable hotspot areas in northern and north-western agricultural areas. I found that in boreal agroecosystems farmland birds favour fields with springtime vegetative cover, especially agricultural grasslands and set-asides. Hence, in the spring cereal dominated Finnish agroecosystems it is the absence of field vegetation that may limit populations of many farmland bird species. It is likely that the decrease of crops providing vegetative cover in the spring, such as permanent grasslands, cultivated grass, and autumn-sown cereals, has greatly contributed to the declines of Finnish farmland birds. Grass crops have persistently declined in Finland as a consequence of specialization in crop production and the large-scale decline in livestock husbandry. Small-scale non-crop habitats, especially ditches and ditch margins, are also important for many bird species in the Finnish agroecosystems, but have dramatically declined during the last decades. A major problem for farmland bird conservation in Finland is the conflict between landscape structure and agricultural management. Areas with mixed and cattle farming are virtually absent from the large agricultural plains of southern and south-western Finland, where the landscape structure is more likely to be favourable for rich farmland bird assemblages. On the other hand, mixed and cattle farming is still rather frequent in northern and central parts of the country, where the landscape structure is not suitable for many farmland specialist birds requiring open landscapes. My results provide useful guidelines for farmland bird conservation, and imply that considerable attention needs to be paid to landscape factors when selecting areas for various conservational management actions, such as agri-environment schemes. Actions promoting the abundance of set-asides, grass crops, and ditches would markedly benefit Finnish farmland bird populations. Organic farming may benefit farmland birds, but it is not clear how general its beneficial effect is in boreal agroecosystems. The most urgent action aiming to preserve farmland biodiversity would be to support re-introducing and sustaining cattle farming by environmental subsidies. This would be especially beneficial in the southern parts of Finland, where the landscape characteristics and abundance of agricultural areas are most suitable for farmland birds and where cattle farming is currently rare.

The community of medium-sized carnivores: the interactions between species, habitats and rabies

The composition of the carnivore community influences the different forms of inter-specific interactions. Furthermore, inter-specific interactions of carnivores have important implications for intra-guild competition, epidemiology and strategies of species-specific population management. Zoonooses, such as rabies, are diseases that can be transmitted from wildlife to people. Knowing the ecological characteristics of the species helps us to choose the right preventive actions and to time them accurately. In this thesis, I have studied how raccoon dogs Nyctereutes procyonoides, European badgers Meles meles, red foxes Vulpes vulpes and domestic cats Felis silvestris catus act as members of carnivore community, and how these interactions relate to the transmission risk of rabies. In the study area, these species form a community of medium-sized and rather generalist predators. They live in the same areas, in spatially and temporally overlapping home ranges and use the same habitats and dens and even have similar diets. However, there is no direct evidence of competition. Shared dens point to good tolerance of other species. Numerous observations of animals moving in each other’s proximity give similar clues. However, overlapping home ranges and similar habitat preferences lead to frequent inter-specific contacts, which increase the risk of possible rabies transmission. Also, the new insight of habitat use gained by this study illustrates the similar favouring of deciduous forests and fields by these sympatric medium-sized carnivores, creating a basis for contact zones, i.e. risky habitats for rabies transmission and spread. This study is so far the only simultaneous radio tracking study of raccoon dogs, badgers, foxes and cats. These results give new insight of the interactions in the carnivore community, as well as of the behaviour of each individual species. Also, these results have significant implications for the planning of rabies control. In order to reach viable management decisions, not only one or two species should be taken into consideration, but the whole community. In particular, this changes the perspective to inter-specific contacts, animal densities, densities of individuals susceptible to diseases and the magnitude of preventive actions. Rabies should be considered as a multi-vector disease, at least in Finland and the Baltic states. It is of interest for disease management to be able to model an epizootic with local parameters to reflect the real situation and also to suite best the local management needs.

Should I stay or should I go? : Reproductive and dispersal strategies of site-specific liverwort species

The area of intensively managed forests, in which required conditions for several liverwort species are seldom found, has expanded over the forest landscape during the last century. Liverworts are very sensitive to habitat changes, because they demand continuously moist microclimate. Consequently, about third of the forest liverworts have been classified as threatened or near threatened in Finland. The general objective of this thesis is to increase knowledge of the reproductive and dispersal strategies of the substrate-specific forest bryophytes. A further aim was to develop recommendations for conservation measures for species inhabiting unstable and stable habitats in forest landscape. Both population ecological and genetic methods have been applied in the research. Anastrophyllum hellerianum inhabits spatially and temporally limited substrate patches, decaying logs, which can be considered as unstable habitats. The results show that asexual reproduction by gemmae is the dominant mode of reproduction, whereas sexual reproduction is considerably infrequent. Unlike previously assumed, not only spores but also the asexual propagules may contribute to long-distance dispersal. The combination of occasional spore production and practically continuous, massive gemma production facilitates dispersal both on a local scale and over long distances, and it compensates for the great propagule losses that take place preceding successful establishment at suitable sites. However, establishment probability of spores may be restricted because of environmental and biological limitations linked to the low success of sexual reproduction. Long-lasting dry seasons are likely to result in a low success of sexual reproduction and decreased release rate of gemmae from the shoots, and consequent fluctuations in population sizes. In the long term, the substratum limitation is likely to restrict population sizes and cause local extinctions, especially in small-sized remnant populations. Contrastingly, larger forest fragments with more natural disturbance dynamics, to which the species is adapted, are pivotal to species survival. Trichocolea tomentella occupies stable spring and mesic habitats in woodland. The relatively small populations are increasingly fragmented with a high risk for extinction for extrinsic reasons. The results show that T. tomentella mainly invests in population persistence by effective clonal growth via forming independent ramets and in competitive ability, and considerably less in sexuality and dispersal potential. The populations possess relatively high levels of genetic diversity regardless of population size and of degree of isolation. Thus, the small-sized populations inhabiting stable habitats should not be neglected when establishing conservation strategies for the species and when considering the habitat protection of small spring sites. Restricted dispersal capacity, also on a relatively small spatial scale, is likely to prevent successful (re-)colonization in the potential habitat patches of recovering forest landscapes. By contrast, random short-range dispersal of detached vegetative fragments within populations at suitable habitat seems to be frequent. Thus, the restoration actions of spring and streamside habitats close to the populations of T. tomentella may contribute to population expansion. That, in turn, decreases the harmful effects of environmental stochasticity.

The range expansion of the European map butterfly in Finland

Climate change will influence the living conditions of all life on Earth. For some species the change in the environmental conditions that has occurred so far has already increased the risk of extinction, and the extinction risk is predicted to increase for large numbers of species in the future. Some species may have time to adapt to the changing environmental conditions, but the rate and magnitude of the change are too great to allow many species to survive via evolutionary changes. Species responses to climate change have been documented for some decades. Some groups of species, like many insects, respond readily to changes in temperature conditions and have shifted their distributions northwards to new climatically suitable regions. Such range shifts have been well documented especially in temperate zones. In this context, butterflies have been studied more than any other group of species, partly for the reason that their past geographical ranges are well documented, which facilitates species-climate modelling and other analyses. The aim of the modelling studies is to examine to what extent shifts in species distributions can be explained by climatic and other factors. Models can also be used to predict the future distributions of species. In this thesis, I have studied the response to climate change of one species of butterfly within one geographically restricted area. The study species, the European map butterfly (Araschnia levana), has expanded rapidly northwards in Finland during the last two decades. I used statistical and dynamic modelling approaches in combination with field studies to analyse the effects of climate warming and landscape structure on the expansion. I studied possible role of molecular variation in phosphoglucose isomerase (PGI), a glycolytic enzyme affecting flight metabolism and thereby flight performance, in the observed expansion of the map butterfly at two separate expansion fronts in Finland. The expansion rate of the map butterfly was shown to be correlated with the frequency of warmer than average summers during the study period. The result is in line with the greater probability of occurrence of the second generation during warm summers and previous results on this species showing greater mobility of the second than first generation individuals. The results of a field study in this thesis indicated low mobility of the first generation butterflies. Climatic variables alone were not sufficient to explain the observed expansion in Finland. There are also problems in transferring the climate model to new regions from the ones from which data were available to construct the model. The climate model predicted a wider distribution in the south-western part of Finland than what has been observed. Dynamic modelling of the expansion in response to landscape structure suggested that habitat and landscape structure influence the rate of expansion. In southern Finland the landscape structure may have slowed down the expansion rate. The results on PGI suggested that allelic variation in this enzyme may influence flight performance and thereby the rate of expansion. Genetic differences of the populations at the two expansion fronts may explain at least partly the observed differences in the rate of expansion. Individuals with the genotype associated with high flight metabolic rate were most frequent in eastern Finland, where the rate of range expansion has been highest.

Microarrays in Lung Cancer Research: From Comparative Analyses to Verified Findings

Keuhkosyöpä on yleisimpiä syöpätauteja. Se jaetaan kahteen päätyyppiin: pienisoluiseen ja ei-pienisoluiseen keuhkosyöpään. Ei-pienisoluinen keuhkosyöpä jaetaan lisäksi alatyyppeihin, joista suurimmat ovat levyepiteeli-, adeno- ja suurisoluinen karsinooma. Keuhkosyövän tärkein riskitekijä on tupakointi, mutta muutkin työ- ja elinympäristön altisteet, kuten asbesti, voivat johtaa syöpään. Väitöstyössä tutkittiin kahdenlaisten keuhkosyöpäryhmien erityispiirteitä. Työssä kartoitettiin, onko löydettävissä muutoksia, jotka erottavat asbestikeuhkosyövät muista syövistä sekä luuytimeen varhaisessa vaiheessa leviävät keuhkosyövät leviämättömistä syövistä. Tutkimusten ensimmäisessä vaiheessa käytettiin mikrosirupohjaisia menetelmiä, jotka mahdollistavat jopa kaikkien geenien tarkastelun yhden kokeen avulla. Vertailevien mikrosirututkimusten avulla on mahdollista paikantaa geenejä tai kromosomialueita, joiden muutokset erottelevat ryhmät toisistaan. Asbestiin liittyvissä tutkimuksissa paikannettiin kuusi kromosomialuetta, joissa geenien kopiolukumäärän sekä ilmenemistason muutokset erottelivat potilaat altistushistorian mukaan. Riippumattomilla laboratoriomenetelmillä tehtyjen jatkoanalyysien avulla pystyttiin varmistamaan, että 19p-alueen häviämä oli yhteydessä asbestialtistukseen. Työssä osoitettiin myös, että 19p-alueen muutoksia voidaan indusoida altistamalla soluja asbestille in vitro. Tutkimuksessa saatiin lisäksi viitteitä asbestispesifisistä muutoksista signaalinvälitysreiteissä, sillä yhdessä toimivien geenien ilmentymisessä havaittiin eroja asbestille altistuneiden ja altistumattomien välillä. Vertailemalla luuytimeen syövän aikaisessa vaiheessa levinneiden ja leviämättömien keuhkoadenokarsinoomien muutosprofiileita toisiinsa, paikannettiin viisi aluetta, joilla geenien kopiolukumäärä- sekä ilmenemistason muutokset erottelivat ryhmät toisistaan. Jatkoanalyyseissä havaittiin, että 4q-alueen häviämää esiintyi adenokarsinoomien lisäksi levyepiteelikarsinoomiin, jotka olivat levinneet luuytimeen. Myös keuhkosyöpien aivometastaaseissa alue oli toistuvasti hävinnyt. Väitöstyön tutkimukset osoittavat, että vertailevien mikrosiruanalyysien avulla saadaan tietoa syöpäryhmien erityispiirteistä. Työssä saadut tulokset osoittavat, että 19p-alueen muutokset ovat tyypillisiä asbestikeuhkosyöville ja 4q-alueen muutokset luuytimeen aikaisessa vaiheessa leviäville keuhkosyöville.

Genomic Profiling of Gastric Cancer

Gastric cancer is the fourth most common cancer and the second most common cause of cancer-related death worldwide. Due to lack of early symptoms, gastric cancer is characterized by late stage diagnosis and unsatisfactory options for curative treatment. Several genomic alterations have been identified in gastric cancer, but the major factors contributing to initiation and progression of gastric cancer remain poorly known. Gene copy number alterations play a key role in the development of gastric cancer, and a change in gene copy number is one of the fundamental mechanisms for a cancer cell to control the expression of potential oncogenes and tumor suppressor genes. This thesis aims at clarifying the complex genomic alterations of gastric cancer to identify novel molecular biomarkers for diagnostic purposes as well as for targeted treatment. To highlight genes of potential biological and clinical relevance, we carried out a systematic microarray-based survey of gene expression and copy number levels in primary gastric tumors and gastric cancer cell lines. Results were validated using immunohistochemistry, real-time qRT-PCR, and affinity capture-based transcript (TRAC) assay. Altogether 192 clinical gastric tissue samples and 7 gastric cancer cell lines were included in this study. Multiple chromosomal regions with recurrent copy number alterations were detected. The most frequent chromosomal alterations included gains at 7q, 8q, 17q, 19q, and 20q and losses at 9p, 18q, and 21q. Distinctive patterns of copy number alterations were detected for different histological subtypes (intestinal and diffuse) and for cancers located in different parts of the stomach. The impact of copy number alterations on gene expression was significant, as 6-10% of genes located in the regions of gains and losses also showed concomitant alterations in their expression. By combining the information from the DNA- and RNA-level analyses many novel gastric cancer-related genes, such as ALPK2, ENAH, HHIPL2, and OSMR, were identified. Independent genome-wide gene expression analysis of Finnish and Japanese gastric tumors revealed an additional set of genes that was differentially expressed in cancerous gastric tissues compared with normal tissue. Overexpression of one of these genes, CXCL1, was associated with an improved survival of gastric cancer. Thus, using an integrative microarray analysis, several novel genes were identified that may be critically important for gastric carcinogenesis. Further studies of these genes may lead to novel biomarkers for gastric cancer diagnosis and targeted therapy.

The Molecular Basis of Hydrolethalus Syndrome

Hydrolethalus syndrome (HLS) is a severe fetal malformation syndrome that is inherited by an autosomal recessive manner. HLS belongs to the Finnish disease heritage, an entity of rare diseases that are more prevalent in Finland than in other parts of the world. The phenotypic spectrum of the syndrome is wide and it is characterized by several developmental abnormalities, including hydrocephalus and absent midline structures in the brain, abnormal lobation of the lungs, polydactyly as well as micrognathia and other craniofacial anomalies. Polyhydramnios are relatively frequent during pregnancy. HLS can nowadays be effectively identified by ultrasound scan already at the end of the first trimester of pregnancy. One of the main goals in this study was to identify and characterize the gene defect underlying HLS. The defect was found from a previously unknown gene that was named HYLS1. Identification of the gene defect made it possible to confirm the HLS diagnosis genetically, an aspect that provides valuable information for the families in which a fetus is suspected to have HLS. Neuropathological findings of mutation confirmed HLS cases were described for the first time in detail in this study. Also, detailed general pathological findings were described. Since HYLS1 was an unknown gene with no relatives in the known gene families, many functional studies were performed in order to unravel the function of the gene and of the protein it codes for. Studies showed, for example, that the subcellular localization of the HYLS1 protein was different when the normal and the defective forms were compared. In addition, HYLS1 was shown to possess transactivation potential which was significantly diminished in the defective form. According to the results of this study it can be stated that HYLS1 most likely participates in transcriptional regulation and also in the regulation of cholesterol metabolism and that the function of HYLS1 is critical for normal fetal development.

Country-scale carbon accounting of the vegetation and mineral soils of Finland

The increase in global temperature has been attributed to increased atmospheric concentrations of greenhouse gases (GHG), mainly that of CO2. The threat of severe and complex socio-economic and ecological implications of climate change have initiated an international process that aims to reduce emissions, to increase C sinks, and to protect existing C reservoirs. The famous Kyoto protocol is an offspring of this process. The Kyoto protocol and its accords state that signatory countries need to monitor their forest C pools, and to follow the guidelines set by the IPCC in the preparation, reporting and quality assessment of the C pool change estimates. The aims of this thesis were i) to estimate the changes in carbon stocks vegetation and soil in the forests in Finnish forests from 1922 to 2004, ii) to evaluate the applied methodology by using empirical data, iii) to assess the reliability of the estimates by means of uncertainty analysis, iv) to assess the effect of forest C sinks on the reliability of the entire national GHG inventory, and finally, v) to present an application of model-based stratification to a large-scale sampling design of soil C stock changes. The applied methodology builds on the forest inventory measured data (or modelled stand data), and uses statistical modelling to predict biomasses and litter productions, as well as a dynamic soil C model to predict the decomposition of litter. The mean vegetation C sink of Finnish forests from 1922 to 2004 was 3.3 Tg C a-1, and in soil was 0.7 Tg C a-1. Soil is slowly accumulating C as a consequence of increased growing stock and unsaturated soil C stocks in relation to current detritus input to soil that is higher than in the beginning of the period. Annual estimates of vegetation and soil C stock changes fluctuated considerably during the period, were frequently opposite (e.g. vegetation was a sink but soil was a source). The inclusion of vegetation sinks into the national GHG inventory of 2003 increased its uncertainty from between -4% and 9% to ± 19% (95% CI), and further inclusion of upland mineral soils increased it to ± 24%. The uncertainties of annual sinks can be reduced most efficiently by concentrating on the quality of the model input data. Despite the decreased precision of the national GHG inventory, the inclusion of uncertain sinks improves its accuracy due to the larger sectoral coverage of the inventory. If the national soil sink estimates were prepared by repeated soil sampling of model-stratified sample plots, the uncertainties would be accounted for in the stratum formation and sample allocation. Otherwise, the increases of sampling efficiency by stratification remain smaller. The highly variable and frequently opposite annual changes in ecosystem C pools imply the importance of full ecosystem C accounting. If forest C sink estimates will be used in practice average sink estimates seem a more reasonable basis than the annual estimates. This is due to the fact that annual forest sinks vary considerably and annual estimates are uncertain, and they have severe consequences for the reliability of the total national GHG balance. The estimation of average sinks should still be based on annual or even more frequent data due to the non-linear decomposition process that is influenced by the annual climate. The methodology used in this study to predict forest C sinks can be transferred to other countries with some modifications. The ultimate verification of sink estimates should be based on comparison to empirical data, in which case the model-based stratification presented in this study can serve to improve the efficiency of the sampling design.